Cumulative exposure to excessive levels of estrogen is a major risk factor for breast cancer. Estrogen and its cellular receptor, estrogen receptor (ER), are involved in regulating normal breast epithelial and tumor cell proliferation, and ER is both a prognostic marker and a therapeutic target in breast cancer treatment. Selective estrogen receptor modulators (SERMs) have been shown to be effective in both preventing and treating ER- positive breast cancers. ER is also a molecular target of phytoestrogens, a group of plant-derived phenolic compounds which are structurally similar to estrogen and SERMs. This raises possibility that intake of foods containing these compounds may help prevent breast cancers. A better understanding of ER functions and the impact of SERMs and phytoestrogens on their molecular mechanisms, therefore, should lead to both better understanding and application of these compounds in cancer prevention. Recently published microarray studies and whole-genome ER binding site mapping experiments suggest that ER can alternatively directly repress the expression of a significant subset of target genes. Little is known regarding the mechanisms of transcriptional repression by ER, although the data indicate that many genes are directly down-regulated following estrogen treatment and the effects of SERMs and phytoestrogens on repressed target gene expression and mechanisms of transcriptional repression by ER are also unclear. The aims of our proposed studies are to identify transcription factors which may facilitate ER-mediated transcriptional repression and to determine the effects of SERMs and phytoestrogens on these and other potential mechanisms of transcriptional repression by ER. These aims and corresponding experiments outlined in this application seek to shed light on a novel aspect of transcriptional regulation by ER, a molecular target of SERMs and phytoestrogens, and the effects of these compounds on newly discovered target mechanisms. Findings from the proposed studies will not only establish a new molecular paradigm for understanding and describing ER and SERM and phytoestrogen functions but will also facilitate future studies on the potential role of SERMs and phytoestrogens and target mechanisms in cancer prevention.